Title

Author

Date of Award

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Dr Leonie Young

Second Supervisor

Professor Arnold Hill

Keywords

Breast Neoplasms, Drug Therapy, Aromatase Inhibitors

Abstract

Introduction

Breast cancer is the second most common cancer in women worldwide. Approximately 80% of breast cancer patients are postmenopausal women and about two thirds of those are diagnosed with hormone receptor positive breast cancer. Therefore, endocrine therapy to block ER activity and signaling is the most successful and most commonly used therapy. Aromatase Inhibitors (Als) are currently one of the most promising treatments for estrogen-receptor positive breast cancer in postmenopausal women. Even though many women initially respond to the treatment, approximately 40% will acquire resistance and relapse within 5 year. The mechanisms involved in the development of resistance to Als however are poorly understood as long-term follow up is only now becoming available.

It is though that the development of resistance and resulting tumour recurrence is due, at least in part, to cellular plasticity leading to a shift in the phenotype of the tumour cell from steroid dependence to steroid independence / growth factor dependence. Consequently, the resistant cancer cells may utilize steroid receptor-independent mechanisms to drive tumour progression.

Aberrant expression of the p l6 0 steroid receptor coactivators SRC-1 and SRC-3 (AIB1) in patients has been associated with resistance to endocrine therapies and the development of tumour recurrence. Although initially described as a nuclear receptor coactivator protein, SRC-1 has been shown to interact with transcription factors running downstream o f an activated MAP kinase pathway. These transcription factor interactions may represent one of the consequences of growth factor pathway cross-talk described in endocrine resistance. Functional interactions between SRC-1 and the Ets family of transcription factors, Ets2 and PEA3 have previously been reported, and this relationship has been shown to be important in tumour progression and the development of metastasis in tamoxifen treated patients.

Hypothesis

The hypothesis of this thesis is to investigate if the steroid receptor coactivator SRC-1 plays an important role in advancing the metastatic phenotype in Aromatase Inhibitor resistance. It will be investigated if such a role is dependent on or independent of estrogen receptor signaling.

Results

The development of Al resistance in cell lines gave rise to a phenotype displaying an increase in motility and invasiveness along with a loss of organisation. Both the resistant cell model and Al resistant tumour samples expressed high levels of the steroid receptor coactivator SRC-1. We found that SRC-1 interacts with the transcription factor Ets to regulate Myc and MMP9 expression and that SRC-1 was required for the aggressive Al resistant phenotype. In patients treated with a first-line Al (n=89), we found that hormone receptor switching between the primary tumour and the resistant metastasis was a common feature of disease recurrence. A significant coassociation between SRC-1 and Ets2 in the nucleus of the recurrent tissue compared with the matched primary tumour was also observed (p=0.0004, n=3). We also observed an increase in Myc and MMP9 protein expression in the recurrent tissue in comparison to the matched primary tumour.

Conclusion

SRC-1 plays a key functional role in the mediation of an Al resistant aggressive phenotype by utilising Ets to regulate Myc and MMP9. Targeting downstream proteins of the SRC-1 signaling pathway may offer clinical potential to treat tumour recurrence.